Effect of APOE Genotype in a Novel Rat Model of Cerebral Amyloid Angiopathy

2023, 2024

Cerebral amyloid angiopathy (CAA) is a disease of blood vessels in the brain that is prevalent in the elderly. CAA causes cognitive impairment and dementia and commonly occurs in patients with Alzheimer’s disease and related disorders (ADRD). CAA arises from the accumulation of aggregated amyloid beta protein in brain blood vessels. This accumulation of brain vascular amyloid causes ischemic strokes and hemorrhages, deleterious events that can cause dysfunction and loss of neurons, contributing to cognitive decline and dementia. Apolipoprotein E (APOE) is a protein involved with lipid metabolism in the body. In the brain, it plays an important function in transporting cholesterol to neuronal cells. There are three forms of APOE in humans (E2, E3, and E4), where the APOE4 isoform significantly increases the risk for both CAA and ADRD. However, the mechanisms of how APOE4 promotes and exacerbates CAA and its downstream detrimental events remain unclear. To better understand the influence of APOE genotype on the emergence and progression of CAA and to effectively evaluate therapeutic interventions for this frequent ADRD condition, appropriate experimental, preclinical animal models are needed. For the past 20 years, most experimental animal model studies designed to address the contributions of APOE genotype to the pathogenesis of CAA and ADRD have largely centered around the use of mice. Although these earlier models have been useful, they come with numerous shortcomings with regard to properly mimicking the human disease condition. Alternatively, rats hold promise for improving our ability to investigate CAA and ADRD since they more closely resemble humans and provide opportunities for better analysis of pathological changes that occur in the brain and cognition. Recently, we have generated new genetically altered rats to investigate CAA. The focus of our project is to use these newly generated rat models to investigate how APOE genotype impacts the onset, progression, and severity of CAA in a manner that more accurately reflects human disease. Successful completion of this work will lead to a more complete understanding of the pathogenic mechanisms that promote CAA and will provide invaluable preclinical models to the scientific field for biomarker development and therapeutic testing.

Funding to Date



Studies of Alternative Neurodegenerative Pathways, Translational


William Van Nostrand, Ph.D.